Methods of converting mixtures of palmitoleic and oleic acid esters to high value products

ABSTRACT

The invention describes methods and systems for making particular organic compounds from unsaturated fatty acids derived from biological materials. Particular embodiments describe synthesizing civetone and olefins from a mixture of palmitoleic and oleic unsaturated fatty acid esters. The inventive methods use reaction steps such as metathesis, cyclization, hydrolysis, and/or decarboxylation.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 61/675,221, filed 24 Jul. 2013.

INTRODUCTION

Currently, most chemical production is based on petrochemical feedstocks(also known as fossil fuels). These feedstocks are obtained from carbonsources that have been buried underground for millions of years. Thesepetrochemical feedstocks are being extracted from their undergroundrepositories and converted into a myriad of chemicals for uses rangingfrom fuel to plastics to commodity chemicals to high value compoundssuch as fragrances. Although techniques for modifying petrochemicalfeedstocks are very well developed, there are serious drawbacks frompetrochemical-based technologies including declining supplies ofpetrochemicals and environmental hazards in extracting thepetrochemicals from underground repositories. In addition, much of thecarbon from the petrochemicals ends up in the atmosphere in the form ofcarbon monoxide (CO) and carbon dioxide (CO₂) which are implicated inglobal warming.

To ameliorate the problems with petrochemicals, great efforts have beenexpended in developing alternatives to petrochemical-based technologies.One such alternative to petrochemical feedstocks are carbon-containingcompounds extracted from recently-living organisms. As organisms such asalgae and plants grow, they extract CO₂ from the atmosphere, thusproviding a major advantage over fossil fuel technology. A challengewith using these organisms to replace fossil fuels is the relative costof growing them and making useful products from these organisms. Thus,there has been a long-standing problem of increasing the value ofproducts obtained from living or recently-living organisms such as algaeand plants. This invention provides new techniques for making high-valueproducts from mixtures of palmitoleic acid esters and oleic acid estersthat are derived from biological materials.

As described in greater detail below, the invention provides a new routeto civetone and olefinic co-products. Civetone is a macrocyclic ketonewhich is used as an ingredient in perfume and fragrance products. Innature, civetone is a pheromone produced by the African Civet. Due tothe limited natural supply, methods of synthesizing civetone have beendeveloped. Known sources of starting materials for synthesizing civetoneinclude compositions high in oleic acid (C18:1; C₁₈H₃₄O₂), such as palmoil, and compositions high in aleuritic acid (C₁₆H₃₂O₅), such asshellac. The current methods for synthesizing civetone have not achieveda high efficiency, with the overall isolated yields for known methods ofsynthesizing civetone from oleic acid ranging from 23-74% in labsettings and yields from aleuritic acid being even lower. The ability toget higher overall yields of selected products is an advantage of somepreferred embodiments of the invention.

Civetone can be synthesized from Omega-7 rich oil, such as, but notlimited to, the commonly known sources sea buckthorn and macadamia nutoil. The monounsaturated fatty composition (C16:1 and C18:1) for Seabuckthorn is around 50% (Yang & Kallio, 2001) and for Macadamia nut oil(Maguire, O'Sullivan, Galvin, O'Connor, & O'Brien, 2004) it isapproximately 80%. In the present invention, ethyl esters of Palmitoleicacid (C16:1) and Oleic acid (C18:1) obtained from Omega-7 rich oilsources can be used as precursors for synthesis of civetone.

Synthesis of ethyl esters is known for the enrichment of Omega-3 fattyacids. Transesterification of Omega-7 fatty acids to produce ethylesters can be done using multiple catalyst/conditions, such as thefollowing catalyst/conditions:

-   -   a) enzymatic (Fjerbaek, Christensen, & Norddahl, 2009)(Modi,        Reddy, Rao, & Prasad, 2007)(Mata, Sousa, Vieira, & Caetano,        2012);

b) acid/base catalyzed (Rodri & Tejedor, 2002)(Alamu, Waheed, &Jekayinfa, 2008); or c) heterogeneous catalyst (Zabeti, Wan Daud, &Aroua, 2009)(Liu, He, Wang, Zhu, & Piao, 2008).

As shown in FIG. 1, ethyl esters of Omega-7 oil can be separated usingone or more separation techniques, such as, but not limited to,molecular distillation. Molecular distillation is a separation techniqueused for separation of fatty acid methyl esters (FAME) in biodieselproduction process. Ethyl esters from Omega-7 rich oil can be separatedinto three fractions (Rossi, Pramparo, Gaich, Grosso, & Nepote,2011)(Tenllado, Reglero, & Torres, 2011):

1) Fuel (such as C10 to C16)

2) Omega-7 (such as C16:1 and C18:1)

3) Omega-3 fractions (such as C20:5 and C22:6).

After molecular distillation, the fuel fraction can provide feed to ahydrotreater for synthesis of high cetane diesel throughhydrodeoxygenation treatments known in the art. The high cetane dieselproduced may be isomerized, using methods known in the art, to give jetfuel. The omega-7 fraction (mono-saturated fatty acids), composed ofPalmitoleic acid (C16:1) and Oleic acid (C18:1), is a commercial productwith many potential uses in the health industry. Omega-7 (Palmitoleicacid) is found in human skin sebum and is known to decline with age(Wille & Kydonieus, 2003). Omega 7 supplements comprising sea buckthornoil are currently available in the market as a health product for skinand hair (contains approximately 30% Omega 7)(Yang & Kallio, 2001).Omega 7 ethyl esters can substitute for sea buckthorn oil in products,and provide an advantage due to the fact that esters can provide ahigher purity not currently available in the market (Rüsch gen. Klaas &Meurer, 2004). In preferred embodiments of the present invention, theOmega-7 rich fraction is used for synthesis of civetone by olefinmetathesis.

PRIOR ART

Prior Art: Known Method of Synthesizing Civetone from Palm Oil

In 1994 (Choo, Ooi, & Ooi, 1994), synthesis of Civetone was reportedfrom Palm oil. In this process Oleic acid (C18:1) was obtained from Palmoil by hydrolytic splitting with 99% purity. See FIG. 2. The pure Oleicacid was esterified under acidic conditions using concentrated sulfuricacid at 110° C. Self-metathesis of ethyl oleate was performed using WCl₆and SnMe₄ to give two products, 9-Octadecene and Diethyl9-Octadecenedioate, with almost quantitative yields of 97 and 99%respectively. Silica-gel chromatography was used to separate the twoproducts. The Diethyl 9-Octadecenedioate was cyclized using basecatalyzed Dieckmann Condensation under inert conditions. DieckmannCondensation was carried out under argon using potassium hydride (KH) indry THF at 55° C. for 3 hours to give2-ethoxycarbonyl-9-cycloheptadecenone with 63% yield which was purifiedby silica-gel chromatography. Civetone was synthesized by hydrolysisfollowed by decarboxylation of 2-ethoxycarbonyl-9-cycloheptadecenoneusing 5% NaOH/THF/Ethanol with 93% yield which was also purified bysilica-gel chromatography.

Prior Art: Known Methods of Ethenolysis of Methyl Oleate and Synthesisof Civetone Using Methyl 9-Decenoate

Ethenolysis of Methyl Oleate

In 2011, ethenolysis of methyl oleate (Thomas, Keitz, Champagne, &Grubbs, 2011) was performed using N-Aryl,N-alkyl N-heterocyclic carbene(NHC) ruthenium metathesis catalysts with 95% selectivity for terminalolefins.

Ethenolysis of methyl oleate can be performed using First GenerationGrubb's catalyst (Burdett et al., 2004) or in a microbial system (Park,Van Wingerden, Han, Kim, & Grubbs, 2011) to give 1-Decene and Methyl9-Decenoate as products. See FIG. 3.

Synthesis of Civetone using Methyl 9-Decenoate

In 2000, Ti-Claisen condensation of Methyl 9-Decenoate followed by anintramolecular metathesis reaction was used for synthesis of civetone(Hamasaki, Funakoshi, Misaki, & Tanabe, 2000). See FIG. 4.

Ti-Claisen condensation of Methyl 9-Decenoate was carried using TiCl₄and Bu₃N at 0-5° C. for 1 hour to give β-ketoester as a product with 93%yield. The β-ketoester was then allowed to undergo intramolecularmetathesis using Grubb's reagent at 110° C. to give2-methoxycarbonyl-9-cycloheptadecenone with 84% yield. The intermediate2-methoxycarbonyl-9-cycloheptadecenone gives Civetone after hydrolysisfollowed by decarboxylation with 95% yield.

SUMMARY

The invention describes certain naturally-derived (bio-based) productsand systems and methods for synthesizing civetone and other productsfrom an omega-7 containing composition. The term “bio-based” or“naturally-derived” means that the compounds are synthesized fromrecently-living biological materials rather than petrochemicalfeedstocks. In this way, the compounds and methods offer a significantadvantage over petro-based components in that they remove carbon fromthe atmosphere. Practically, bio-based materials can be distinguishedfrom petrochemical-based materials by the well known techniques of ¹⁴Cdating. Bio-based materials will have significant levels of ¹⁴C that aretypical of biological material that was living within the past fewhundred years. In contrast, petro-based compounds will have essentiallyzero ¹⁴C.

In a first aspect (see FIG. 5), the invention provides a method ofconverting a mixture comprising derivatives of palmitoleic acid andoleic acid to useful products including olefinic hydrocarbons,comprising: reacting a composition comprising an ester of palmitoleicacid and an ester of oleic acid in a metathesis reaction to produce afirst reaction mixture; reacting at least a portion of the firstreaction mixture, or derivatives thereof, in a cyclization reaction toproduce a second reaction mixture; hydrolyzing and decarboxylating atleast a portion of the second reaction mixture, or derivatives thereof,to produce a third reaction mixture comprising civetone. The phrase “orderivatives thereof” means that the reaction mixtures can be modified bytreatments, such as transesterifications, that do not have a significantdeleterious effect on subsequent synthesis steps. This method yieldscivetone along with at least one olefinic compound selected from thegroup of Olefin D (C₁₄H₂₈ see FIG. 6), and Olefin C (C₁₆H₃₂ see FIG. 6),and 1-Octene (C₈H₁₆). In practice, of course, any of the reactionco-products can be separated or used as intermediates in furtherreactions—products that are separated or consumed as intermediates in afurther reaction are still included in calculations of yield andselectivity.

The “esters” referred to are generally made by esterification ortransesterification of precursor composition comprising palmitoleic acidand oleic acid. A preferred precursor composition comprises a mixture ofpalmitoleic acid C16:1 (C₁₆H₃₀O₂) and oleic acid C18:1 (C₁₈H₃₄O₂), whichis a mixture that can be obtained in an extract from sources such asalgae, sea buckthorn, and macademia. In one preferred embodiment, theprecursor composition is derived from algae.

In some preferred embodiments, the esters are produced by esterificationor transesterification in the presence of a catalyst such as anenzymatic, acidic, basic, and/or heterogeneous catalyst. In someembodiments the esters comprise methyl esters or ethyl esters.

In some of the inventive aspects, the invention can be furthercharacterized one or more of any of the following: the palmitoleic acidand oleic acid are present in the precursor composition in at least 50mass % as a percentage of the total mass of unsaturated fatty acids, insome embodiments, at least 80%, and in some embodiments at least 90% asa percentage of the total mass of unsaturated fatty acids. Likewise, thecomposition of esters preferably contains at least 50 mass % (in someembodiments at least 80%, or at least 90%) of C16palmitoleic-acid-derived esters and C18 oleic-acid-derived esters as amass percentage of all fatty acid esters present in the composition. Themass percent of palmitoleic acid (or the corresponding esters) as apercent of the sum of palmitoleic acid plus oleic acid (or thecorresponding esters) is preferably in the range of 20 to 80%, in someembodiments 30 to 70%, in some embodiments 40 to 60%, in someembodiments, 20 to 50%, in some embodiments 50 to 80%. Thesecharacteristics can be present individually or in combination.

In some embodiments, the precursor composition or composition comprisesabout equal parts palmitoleic acid and oleic acid or (in thecomposition) their corresponding fatty acid esters (i.e., each is withinthe range of 45 to 55% of their total mass). In some embodiments, theprecursor composition or composition comprises a greater portion ofpalmitoleic acid (or esters) than oleic acid (or esters). In someembodiments, the composition comprises a greater portion of oleic acidester(s) than palmitoleic acid ester(s). In some preferred embodiments,the C16 and C18 fatty acids or corresponding esters in the precursorcomposition or composition comprises at least 50 mass % (absolute) ofthe total mass of the precursor composition or composition, in someembodiments at least 70% or at least 80%, and in some embodiments up to99% or 100%.

At any stage of the method, selected products can be separated orpurified by known methods; for example, silica gel chromatography orHPLC. The invention includes any of the products or reaction mixtures inpurified form. For example, any of the chemical compounds can beobtained in forms that are at least 50 mass % pure (i.e., no more than50 mass % of components other than those listed in a claim). Forexample, if a mixture is described as “comprising 1-octene, 1-decene,and ethyl 9-decenoate,” then the invention also includes (in morespecific embodiments) a mixture comprising at least 50 mass % of1-octene, 1-decene, and ethyl 9-decenoate. Likewise, the inventionincludes compositions comprising at least 50 mass % of any of thespecific products and intermediates described herein, since it iscontemplated that any of the products or intermediates can be isolated.In some preferred embodiments, any of the compounds or mixtures are atleast 80% (by mass) pure, in some embodiments at least 99% pure.

In some embodiments, the metathesis reaction is a self-metathesisreaction producing a reaction mixture comprising C₁₈H₃₆, C₁₄H₂₈, andC₂₂H₄₀O₄. In some embodiments, the metathesis reaction is across-metathesis reaction producing a reaction mixture comprising C₁₆H₃₂and C₂₂H₄₀O₄. In some embodiments, the metathesis reaction comprises acatalytic system selected from the group consisting of: WCl₆/Me₄Sn;Heterogeneous Re₂O₇/Al₂O₃ (rhenium oxide on alumina); HeterogeneousRe₂O₇/SiO₂.Al₂O₃/SnBu4; W(O-2,6-C₆H₃X₂)2Cl₄ (X═Cl, Ph) precatalystspromoted with Me₄Sn; B₂O₃.Re₂O₇/Al₂O₃.SiO₂/SnBu₄; WCl₆ and WOCl₄, asprimary catalysts and SnMe₄, PbMe₄, Cp₂TiMe₂, and Cp₂ZrMe₂, ascocatalysts; Ruthenium based catalyst; Grubb's catalyst firstgeneration; Grubbs catalyst second generation; and Hoveyda-Grubbscatalyst. In some preferred embodiments, the metathesis catalystcomprises rhenium oxide, preferably supported on alumina or analuminosilicate.

In some embodiments, the cyclization reaction comprises Dieckmanncondensation. In some embodiments, the cyclization reaction is carriedout with metal hydrides under inert conditions. In some embodiments, thecyclization reaction is carried out with TiO₂ doped with alkali oralkaline earth metal oxides in gaseous phase reaction. In someembodiments, the cyclization reaction comprises Ti-Dieckmann orTi-Claisen condensation.

In some embodiments, civetone is extracted from the product mixtureusing ether. In further embodiments, the extracted civetone can befurther purified, for example, by using silica-gel chromatography. Insome embodiments, the Ti-Dieckmann cyclization forms a reaction mixturecomprising 34-membered macrocyclic ketones. In some embodiments, themethod includes a hydrogenation reaction of the C₂₂H₄₀O₄ to produce areaction mixture and followed by a cyclization step to producedihydrocivetone (cycloheptadecanone).

In another embodiment, fatty acid esters of palmitoleic acid and oleicacid are reacted with ethene to produce a reaction mixture; andsubsequently reacting at least a portion of this reaction mixture (or aderivative thereof) in a condensation reaction; and then conducting asecond metathesis reaction, followed by hydrolysis and decarboxylationto produce civetone and 1-Octene (C₈H₁₆).

In some embodiments, the metathesis reaction with ethene produces amixture comprising 1-Octene (C₈H₁₆), 1-Decene (C₁₀H₂₀), and ethyl9-decenoate (C₁₂H₂₂O₂). In some embodiments the condensation reaction isa Ti-Claisen condensation with a catalysis system selected from thegroup consisting of: TiCl₄—Bu₃N, Pentafluorophenylammonium Triflate, andMgBr₂.OEt₂ in DIPEA. In some embodiments, the metathesis reaction of thecondensation produces ethene and a macrocyclic compound. In someembodiments, the macrocylcic compound is2-ethoxycarbonyl-9-cycloheptadecenone. In some preferred embodiments,the ethene produced is recycled to the step of reacting the esters in ametathesis reaction with ethene. In some embodiments, the condensationproduct comprises a beta-ketoester. In further embodiments, thebeta-ketoester can be purified, for example by extraction ether andoptional additional steps such as chromatography, for example,silica-gel chromatography.

In further aspects of the invention, the invention provides a method ofproducing olefins. In this method, fatty acid esters of the unsaturatedfatty acids C16:1 (C₁₆H₃₀O₂) and C18:1 (C₁₈H₃₄O₂) are reacted in ametathesis reaction to produce a reaction mixture comprising C₁₈H₃₆,

C₁₄H₂₈, C₁₆H₃₂ and C₂₂H₄₀O₄. The invention also includes compositionsthat comprise a mixture of the biobased olefins Olefin E (C₁₈H₃₆ seeFIG. 6), Olefin D (C₁₄H₂₈ see FIG. 6), and Olefin C (C₁₆H₃₂ see FIG. 6).The invention further includes compositions comprising the individualbiobased Olefin C, Olefin D and mixtures thereof, made by methods of thepresent invention. In some preferred embodiments the compositioncomprises at least 10% of Olefin C or Olefin D as a percentage of allolefins in a composition; in some embodiments at least and 10% of OlefinC and at least 10% Olefin D; in some embodiments at least 20% of OlefinC or Olefin D; at least 20% of Olefin C and at least 20% of Olefin D; insome embodiments, 5% to 50% of Olefin C; in some embodiments 5% to 50%of Olefin D; all as a percentage of the total mass of olefins in thecomposition. In some preferred embodiments, the composition comprises atleast 5 mass % of olefins; at least 10 mass % olefins; at least 20 mass% olefins; or at least 50 mass % based on total mass of the composition.In each case, the olefins are biobased which is a significant advantageover petrochemical derived olefins. The compositions can be used in thesynthesis of polymers or chemical compounds, and can be used as a fueladditive, for example, to increase octane rating.

In any of its aspects, the invention may also be characterized byyields. In each case, yield is calculated based on carbon in theselected product or intermediate and in the monounsaturated fatty acidesters present in a starting material composition. In the reactionscarried out using metathesis of the palmitoleic and oleic acid esters,the yield of Diester F (see FIG. 6 below) is preferably greater than20%, more preferably at least 30%, in some embodiments in the range of30 to about 60%, and in some embodiments 40 to 55%. In the reactionscarried out using metathesis of the palmitoleic and oleic acid esters,the yield of the sum of Olefins C, D, and E (see FIG. 6 below) ispreferably at least 20%, more preferably at least 30%, in someembodiments 30 to 44%, in some embodiments 35 to 43%, and in someembodiments 38 to 43%. In some embodiments, the yield of Olefin C is atleast 5%, in some embodiments at least 10%, in some embodiments, atleast 15%, in some embodiments in the range of 10% to 20%. In someembodiments, the yield of Olefin D is at least 5%, in some embodimentsat least 10%, in some embodiments, at least 15%, in some embodiments atleast 20%, in some embodiments at least 25%, in some embodiments in therange of 10% to about 38%, in some embodiments in the range of 10% to30%, in some embodiments in the range of 15% to 25%. Note that, usingthe above definition of yield, in the noninventive case of pure oleicacid ester as the starting material, the maximum theoretical yields ofDiester F and Olefin E would be 55 and 45%, respectively. For thecyclization of Diester F, the yield of cyclized intermediate ispreferably at least 60%, in some embodiments in the range of 60 to 95%.For the combined steps of hydrolysis and decarboxylation the yield ofcivetone is preferably at least 60%, in some embodiments in the range of60 to 95%.

In the reactions carried out using metathesis with ethene, the yield ofethyl 9-decenoate is preferably at least 30%, more preferably at least40%, in some embodiments in the range of 30 to about 65%, in someembodiments 35 to 60% (carbon in ethyl 9-decenoate divided by carbon instarting materials. Note that, using the present carbon-baseddefinition, for the noninventive case of pure oleic acid the maximumtheoretical yield of ethyl 9-decenoate is 55%. The yield of 1-octene ispreferably at least 5%, in some embodiments at least 10%, in someembodiments at least 15%, in some embodiments at least 20%, in someembodiments in the range of 10 to 40%, in some embodiments 10 to 35%, insome embodiments 15 to 30%. The yield of 1-decene is preferably at least5%, in some embodiments at least 10%, in some embodiments at least 15%,in some embodiments at least 20%, in some embodiments in the range of 10to 40%, in some embodiments 10 to 35%, in some embodiments 15 to 30%.The yield of the condensation of ethyl 9-decenoate is preferably atleast 60%, in some embodiments 60 to 95%. The yield of the cyclizedcompound from metathesis of the beta-ketoester is civetone is preferablyat least 60%, in some embodiments in the range of 60 to 95%. For thecombined steps of hydrolysis and decarboxylation the yield of civetoneis preferably at least 60%, in some embodiments in the range of 60 to95%.

In preferred embodiments, the invention has an overall yield, based oncarbon in the products (civetone plus olefinic hydrocarbons) divided bythe sum of carbon in the palmitoleic acid ester and oleic acid esterstarting materials of greater than 25%, preferably greater than 50%,preferably greater than 60%, in some embodiments in the range of 40% to80%, in some embodiments greater than 60% to 95%, in some embodimentsgreater than 60% to 85%, in some embodiments at least 70%, in someembodiments 75 to 90%.

In another aspect, the invention provides a method of producingα-olefins, comprising: producing esters from an composition comprisingat least 50 mass % of palmitoleic acid and oleic acid; and reacting atleast a portion of the esters in a metathesis reaction with ethene toproduce a reaction mixture comprising 1-Octene (C₈H₁₆), 1-Decene(C₁₀H₂₀), and ethyl 9-decenoate (C₁₂H₂₂O₂).

In yet another aspect, the invention provides a method of synthesizingdihydrocivetone. In this method, civetone is made as described hereinand then hydrogenated to produce dihydrocivetone.

In yet another aspect, the invention provides a method of synthesizingcyclopropanated civetone. In this method, civetone is made as describedherein and then reacted in a Simmons-Smith reaction using ZnCu and CH₂I₂to produce cyclopropanated civetone.

In still further embodiments, certain melanin production inhibitors(described herein) are produced. In some embodiments, an acyloincondensation of diethyl 9-octadecenedioate produces a 2-hydroxymacrocyclic ketones which is subsequently converted to melaninproduction inhibitors. In some embodiments, reducing civetone producesmelanin production inhibitors. The reduction may include hydrogenationto make civetol.

In various embodiments, the invention can provide advantages such as:the production of civetone and other high value products fromalgae-derived products; greater efficiency in fully utilizing startingmaterials; the ability to make valuable products such as olefins,polyolefins, and precursors for lubricants, olefins, polymers, andplasticizers; and the synthesis of environmentally-friendly, biobasedolefins.

As is standard patent terminology, the term “comprising” means“including” and permits the presence of additional components. Where theinvention is characterized as “comprising” it should be understand thatthe invention, in narrower embodiments, can alternatively becharacterized as “consisting essentially of” or “consisting of” in placeof “comprising.” Such language limits the invention to the namedcomponents plus components that do not materially degrade the propertiesof the invention, or narrow the invention to only the stated components,respectively. In the descriptions of the invention, the phrase “such as”should be understood as not limiting but only providing somenon-limiting examples.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates examples of synthesis of esters from oil andseparation into fractions based on fatty acid chain length.

FIG. 2 illustrates a known method of synthesizing civetone from palmoil.

FIG. 3 illustrates a known method for the ethenolysis of methyl oleate.

FIG. 4 illustrates a known method of synthesizing civetone from methyl9-decenoate.

FIG. 5 illustrates a method for synthesizing civetone

FIG. 6 illustrates products produced in the Metathesis of Palmitoleicacid and Oleic acid.

FIG. 7 is a side-by-side comparison of metathesis stage of a prior artprocess of synthesizing civetone from palm oil (left) and the inventionmethod (1) of synthesizing civetone and new polyolefin products fromOmega-7 rich oil (right).

FIG. 8 illustrates ethenolysis of a mixture of ethyl esters ofPalmitoleic acid (C16:1) and Oleic acid (C18:1).

FIG. 9 illustrates metathesis, hydrolyzation, and decarboxylation tomake civetone.

FIG. 10 illustrates products from metathesis reactions of Omega-7fraction in invention method 1.

FIG. 11 illustrates alkylation of civetone macrocycle.

FIG. 12 illustrates the synthesis of melanin-production-inhibitingproducts from the acyloin condensation of civetone.

DETAILED DESCRIPTION

In some preferred embodiments, a mixture comprising Palmitoleic acid(C16:1) and Oleic acid (C18:1) is used as a precursor for synthesis ofCivetone. Preferably, the mixture of palmitoleic acid and oleic acid isobtained by transesterification of an Omega-7 rich oil followed bymolecular distillation and is termed “the Omega-7 rich fraction”.

Metathesis of Palmitoleic Acid and Oleic Acid:

Methathesis:

A fraction of fatty acids that can be obtained from biomaterials such asalgae or plants is a mixture of ethyl esters Palmitoleic acid (C16:1)and Oleic acid (C18:1). The metathesis of this composition will producea unique mixture of products, not available through prior art methods.Referring to FIG. 6, the Omega 7 fraction self-metathesis of thePalmitoleic acid ester (A) will yield olefin (D), and Diethyl ester (F)as products. The products will also include self-metathesis products ofthe Oleic acid esters (B), which are olefin (E) and Diethyl ester (F).The Omega 7 fraction will also undergo a cross metathesis reactionbetween the Palmitoleic acid ester (A) and the Oleic acid ester (B) togive olefin (C), a product not available through prior art methods, andDiethyl ester (F).

The Palmitoleic acid of the Omega-7 rich fraction is derived fromsources such as sea buckthorn and macadamia oil, but not palm oil.Therefore the olefin metathesis reaction of the Omega-7 rich oil willgive unique products which are not obtainable by the prior art methodscomprising olefin metathesis of ethyl oleate obtained from palm oil, asshown in FIG. 7.

Cyclization:

The diethyl ester (product F in FIG. 6) produced from the metathesisstage can be cyclized using Dieckmann condensation or its variant.

Hydrolysis and Decarboxylation:

The cyclized compound can be hydrolyzed and decarboxylated to formcivetone.

Ethenolysis:

Ethenolysis comprises a cross-metathesis reaction involving ethene.According to some preferred embodiments of the invention, a mixture ofethyl esters of Palmitoleic acid (C16:1) and Oleic acid (C18:1) aresubjected to conditions of ethenolysis to yield a mixture of α-olefins(1-Octene and 1-Decene) and Methyl 9-Decenoate. See FIG. 8. The 1-Octeneis a product unique to ethenolysis of Palmitoleic acid (C16:1). In theinventive method, Ethyl 9-Decenoate and 1-Decene will also form from themixture of Palmitoleic and Oleic acid ethyl esters. Prior art methodsusing Oleic acid esters (Methyl Oleate) as the starting material onlyproduce Methyl 9-Decenoate and 1-Decene.

Condensation:

The Ethyl 9-Decanoate (see above) can be subjected to a Claisencondensation.

Intramolecular Metathesis:

The product of the condensation stage can be subjected to anintramolecular metathesis reaction to produce ethane gas and amacrocyclic compound, such as 2-ethoxycarbonyl-9-cycloheptadecenone. Theethene gas can be recycled to the ethenolysis step for use in theethenolysis reaction.

Hydrolyization and Decarboxylation:

The macrocyclic beta-ketoester compound can be hydrolyzed anddecarboxylated to form civetone.

EXAMPLES Contemplated Invention Embodiment 1 Example

Metathesis of Omega-7 fraction:

The 2^(nd) generation ruthenium catalyst (IMesH₂)(PCy₃)(Cl)₂Ru=CHPhwhere IMesH₂ is 1,3-dimesityl-4,5-di-hydroimidazol-2-ylidene with itsbulky N-heterocyclic carbine (NHC) ligand (Dinger & Mol, 2002) is knownto perform with high turnover numbers and gives the product with highselectivity and can be an ideal catalyst for metathesis of Omega-7fraction. The reaction will be carried out in inert atmosphere at about55° C. The products Diethyl 9-Octadecenedioate and mixture of olefinsformed in this reaction will be purified by silica-gel chromatography.See FIG. 10.

Metathesis Catalysts:

In oleochemistry, olefin metathesis is well known and it includesself-metathesis (SM), cross-metathesis (CM), ring closing metathesis(RCM), ring-opening metathesis (ROM) and ROM polymerization (ROMP) aswell as acyclic diene metathesis polymerization (ADMET) reactions. Avariety of catalytic systems can be utilized for metathesis of Omega-7fraction to achieve selectivity and high turnover numbers, such as:

-   -   WCl₆/Heterogeneous Re₂O₇/A_(12O3)    -   Heterogeneous Re₂O₇/SiO₂.Al₂O₃/SnBu₄    -   W(O-2,6-C₆H₃X₂)2Cl₄ (X═Cl, Ph) precatalysts promoted with Me₄Sn    -   B₂O₃.Re₂O₇/Al₂O₃.SiO₂/SnBu₄    -   WCl₆ and WOCl₄, as primary catalysts and SnMe₄, PbMe₄, Cp₂TiMe₂,        and Cp₂ZrMe₂, as cocatalysts,    -   Ruthenium based catalysts (Grubb's catalyst first, second        generation and Hoveyda-Grubbs catalyst).

Table 1 illustrates examples of catalysts which can be used to performmetathesis of the omega-7 fraction (Mol, 2002).

TABLE 1 Examples of catalyst systems for the metathesis of (m)ethyloleate Catalyst Ester/metal atom^(a) T/° C. t^(b)/h TON^(c) Ref.Homogeneous systems WCl₆/Me₄Sn  75 110 2  38 26W(OC₆H₃Cl₂-2,6)₂Cl₄/Bu₄Pb  50 85 0.5  25 30W(═CHCMe₃)NpCl(OAr)₂(OEt₂)^(d) 100 85 1  32 31 [W]═CHCMe₃ (see formulaI) 300 25 2-3 150 32 [W]═CHCMe₃ (see formula II) 500 25 1 250 33Ru(═CH—CH═CPh₂)Cl₂(PCy₃)₂ 2 000   20 96 960 34 Ru(═CHPh)Cl₂(PCy₃)₂ 5 500  20 48 2 500   35 [Ru₂]═CHPh(1H, R′ = CF₃) 550 40 1 225 36Ru(═CHPh)Cl₂(H₂IMes)(PCy₃) (IV)^(e) 987 000    55 6 440 000    48Heterogeneous systems Re₂O₂/Al₂O₃/Et₄Sn  60 20 2  3 18Re₂O₇/MoO₃/Al₂O₃/Et₄Sn  60 20 2  30 18 Re₂O₇/B₂O₃/Al₂O₃/Bu₄Sn 120 20 2 50 37 Re₂O₇/SiO₂—Al₂O₃/Bu₄Sn 240 40 2 120 10Re₂O₇/B₂O₃/SiO₂—Al₂O₃/Bu₄Sn^(f) 480 20 2 160 38Re₂O₇/B₂O₃/SiO₂—Al₂O₃/Bu₄Sn^(g) 200 80 2  90 39 CH₃ReO₃/SiO₂—Al₂O₃ 10025 2  27 40 MoO₃/SiO₂/(CO, hv)/cyclopropane 250 50 0.17  25 41MoO₃/SiO₂/(CO, laser)/cyclopropane 1 250   40 3 500 10 ^(a)Molar ratio.^(b)t = Time to reach the highest conversion. ^(c)TON = Moles ofsubstrate converted per mol of W. Ru, Re or Mo into reaction products.^(d)Ar = C₆H₃Ph₂-2,6. Np = CH₂CMe₃. ^(e)No solvent. ^(f)Silica-aluminacontaining −25 wt % Al₂O₃. ^(g)Silica-alumina containing 60 wt % Al₂O₃.

Table 1: Examples of catalyst system for metathesis of (m)ethyl oleate

Dieckmann Condensation (Macrocyclization):

Ti-Dieckmann (intramolecular Ti-Claisen) condensation (Hamasaki et al.,2000; Tanabe, Makita, Funakoshi, Hamasaki, & Kawakusu, 2002a; “U.S. Pat.No. 6,861,551.pdf,” n.d.) (TiCl₄/amine) will be used to cyclize Diethyl9-Octadecenedioate. The reaction will be carried out at around 0-5° C.for about 1 hour to give the cyclized product2-ethoxycarbonyl-9-cycloheptadecenone which can be purified bysilica-gel chromatography. The same macro cyclization (Dieckmanncondensation) can be carried out in different conditions:

-   -   KH or NaH (metal hydrides) under inert conditions.    -   TiO₂ doped with alkali or alkaline earth metal oxides (Na₂O or        K₂O) in gaseous phase reaction.    -   ZrCl₄/Bu₃N similar to Ti-Dieckmann condensation.

Hydrolysis and Decarboxylation:

2-ethoxycarbonyl-9-cycloheptadecenone will be refluxed with about 10%NaOH in methanol for about 1 hour to give civetone. After completion ofthe reaction, the reaction mixture will be neutralized using about 10%sulfuric acid. The product will be extracted using ether and can bepurified using silica-gel chromatography.

Hydrolysis and Decarboxylation to form civetone Invention Embodiment 2Example

Ethenolysis of Omega-7 Fraction:

Ethenolysis Reaction of Omega 7 Fraction

Catalysts for Use in Ethenolysis Reaction of Omega 7 Fraction

Ethenolysis of the Omega-7 fraction will be carried out under inertatmosphere with ethylene under conditions of about 150 psi pressure andabout 40° C. (Thomas et al., 2011). N-Aryl,N-alkyl N-heterocycliccarbene (NHC) ruthenium metathesis catalysts are highly selective towardthe ethenolysis of methyl oleate. The catalysts shown in FIG. 16, (A)and (B), give more kinetic selectivity when catalyst loading was 2500ppm due to their sterically demanding ligands. Catalyst A-88%selectivity with 78% yield while catalyst B with 88% selectivity and 77%yield. The products will be separated using silica gel chromatography.

Similar to the Invention embodiment 1 example, a metathesis reaction canbe performed by selecting a catalyst from a variety of metathesiscatalysts (Table 1).

Ti-Claisen Condensation of Ethyl-9-Decenoate:

Ti-Claisen condensation (Hamasaki et al., 2000) will be performed byadding TiCl4 to mixture of Bu₃N and Ethyl decenoate at around 0-5° C.The reaction mixture will be stirred for approximately 1 hour and thenwill be quenched by the addition of water. The product β-ketoester willbe extracted using ether and will be purified by silica-gelchromatography.

Intramolecular Metathesis Reaction, Hydrolysis and Decarboxylation:

The intramolecular metathesis reaction will be similar to the Inventionembodiment 1 example metathesis reaction of an Omega-7 fraction. Themetathesis reaction can be carried out with a selected catalyst asdescribed above. The hydrolysis and decarboxylation will be carried outas described above.

Additional Embodiments

Potential Products from Invention Methods of Synthesizing CivetoneRelevant to Perfume Industry (Macrocyclic Ketone):

The Invention methods disclosed above for synthesizing civetone willgive geometrical isomers of the final product which are Cis-Civetone andTrans-Civetone.

Invention embodiment 1 cyclization mediated Ti-Dieckmann conditions(Tanabe, Makita, Funakoshi, Hamasaki, & Kawakusu, 2002a) willpredominately give Z-isomer of Civetone with approximately 50% yield.Invention embodiment 2 intramolecular metathesis will give a mixture ofE:Z (3:1) isomers of Civetone with 90% yield (Hamasaki et al., 2000).

Ti-Dieckmann cyclization conditions may lead to the formation of34-membered macrocyclic ketones, which have potential uses in theperfume industry. The 34-membered macrocycle can be formed usingTiCl₄-Et₃N, with approximately 14% yield (Tanabe, Makita, Funakoshi,Hamasaki, & Kawakusu, 2002b).

Dihydrocivetone (Cycloheptadecanone) is another macrocyclic ketone withmusk fragrance and can be synthesized by hydrogenation of the finalproduct (Civetone) or by hydrogenation of Diethyl 9-Octadecenedioatefollowed by cyclization.

In 2011 International Flavors & Fragrances Inc. introduced a new classof chemical entities cyclopropanated macrocycles (see U.S. Pat. No.7,943,560) as flavors and fragrances. Civetone (both geometricalisomers) can undergo Simmons-Smith reaction using ZnCu and CH₂I₂ to givecyclopropanated Civetone.

Alkylation:

Muscone (3-Methyl cyclopentadecanone) is methylated macrocycle with muskfragrance. Civetone macrocycle can be alkylated (methylated) to give2-methyl 9-Cycloheptadecen-1-one which can be potential product forperfume industry. Alkylation reaction can be done using Stork enamineconditions to substitute the macrocycles with different alkyl groups.See FIG. 11.

Macrocycles with Potential Melanin Production Inhibition Activity whichcan be Used in Skin Care Products (“Melanin Production Inhibitors,”n.d.):

Diethyl 9-Octadecenedioate product from Invention embodiment 1 canundergo Acyloin condensation to give 2-hydroxy macrocyclic ketones,which can inhibit Melanin production, as shown in FIG. 12. Civetone canbe reduced to give product C, which is a potential melanin productioninhibitor, and hydrogenation of Product C gives Civetol D.

LITERATURE

-   Alamu, 0. J., Waheed, M. a., & Jekayinfa, S. O. (2008). Effect of    ethanol—palm kernel oil ratio on alkali-catalyzed biodiesel yield.    Fuel, 87(8-9), 1529-1533. doi:10.1016/j.fue1.2007.08.011-   Burdett, K. a., Harris, L. D., Margl, P., Maughon, B. R.,    Mokhtar-Zadeh, T., Saucier, P. C., & Wasserman, E. P. (2004).    Renewable Monomer Feedstocks via Olefin Metathesis: Fundamental    Mechanistic Studies of Methyl Oleate Ethenolysis with the    First-Generation Grubbs Catalyst. Organometallics, 23(9), 2027-2047.    doi:10.1021/om0341799-   Choo, Y.-may, Ooi, K. E., & Ooi, I.-hong. (1994). Synthesis of    Civetone from Palm Oil Products, 71(8), 911-913.-   Dinger, M. B., & Mol, J. C. (2002). High Turnover Numbers with    Ruthenium-Based Metathesis Catalysts. Advanced Synthesis &    Catalysis, 344(6-7), 671.    doi:10.1002/1615-4169(200208)344:6/7<671::AID-ADSC671>3.0.00;2-G-   Fjerbaek, L., Christensen, K. V., & Norddahl, B. (2009). A review of    the current state of biodiesel production using enzymatic    transesterification. Biotechnology and bioengineering, 102(5),    1298-315. doi:10.1002/bit.22256-   Hamasaki, R., Funakoshi, S., Misaki, T., & Tanabe, Y. (2000). A    Highly Efficient Synthesis of Civetone, 56, 7423-7425.-   Holley, W., & Spencer, R. D. (1948). Many-membered Carbon Rings. 11.    A New Synthesis of Civetone and dl-Muscone, 30(10), 34-36.-   Liu, X., He, H., Wang, Y., Zhu, S., & Piao, X. (2008).    Transesterification of soybean oil to biodiesel using CaO as a solid    base catalyst. Fuel, 87(2), 216-221. doi:10.1016/j.fue1.2007.04.013-   Maguire, L. S., O'Sullivan, S. M., Galvin, K., O'Connor, T. P., &    O'Brien, N. M. (2004). Fatty acid profile, tocopherol, squalene and    phytosterol content of walnuts, almonds, peanuts, hazelnuts and the    macadamia nut. International journal of food sciences and nutrition,    55(3), 171-8. doi:10.1080/09637480410001725175-   Mata, T. M., Sousa, I. R. B. G., Vieira, S. S., & Caetano, N. S.    (2012). Biodiesel Production from Corn Oil via Enzymatic Catalysis    with Ethanol. Energy & Fuels, 120427072504002. doi:10.1021/ef300319f-   Melanin Production Inhibitors. (n.d.).-   Modi, M. K., Reddy, J. R. C., Rao, B. V. S. K., & Prasad, R. B. N.    (2007). Lipase-mediated conversion of vegetable oils into biodiesel    using ethyl acetate as acyl acceptor. Bioresource technology, 98(6),    1260-4. doi:10.1016/j.biortech.2006.05.006-   Mol, J. C. (2002). Application of olefin metathesis in    oleochemistry: an example of green chemistry. Green Chemistry, 4(1),    5-13. doi:10.1039/b109896a-   Park, C. P., Van Wingerden, M. M., Han, S.-Y., Kim, D.-P., &    Grubbs, R. H. (2011). Low pressure ethenolysis of renewable methyl    oleate in a microchemical system. Organic letters, 13(9), 2398-401.    doi:10.1021/o1200634y-   Rodri, J. J., & Tejedor, A. (2002). Biodiesel Fuels from Vegetable    Oils: Transesterification of Cynara cardunculus L. Oils with    Ethanol, (7), 443-450.-   Rossi, P. C., Pramparo, M. D. C., Gaich, M. C., Grosso, N. R., &    Nepote, V. (2011). Optimization of molecular distillation to    concentrate ethyl esters of eicosapentaenoic (20:5 w-3) and    docosahexaenoic acids (22:6 w-3) using simplified phenomenological    modeling. Journal of the science of food and agriculture, 91(8),    1452-8. doi:10.1002/jsfa.4332-   Rüsch gen. Klaas, M., & Meurer, P. U. (2004). A palmitoleic acid    ester concentrate from seabuckthorn pomace. European Journal of    Lipid Science and Technology, 106(7), 412-416.    doi:10.1002/ejlt.200400968-   Tanabe, Y., Makita, A., Funakoshi, S., Hamasaki, R., & Kawakusu, T.    (2002a). Practical Synthesis of (Z)-Civetone Utilizing Ti-Dieckmann,    (5), 4-7.-   Tanabe, Y., Makita, A., Funakoshi, S., Hamasaki, R., & Kawakusu, T.    (2002b). Practical Synthesis of (Z)-Civetone Utilizing Ti-Dieckmann,    (5), 4-7.-   Tenllado, D., Reglero, G., & Torres, C. F. (2011). A combined    procedure of supercritical fluid extraction and molecular    distillation for the purification of alkylglycerols from shark liver    oil. Separation and Purification Technology, 83, 74-81.    Elsevier B. V. doi:10.1016/j.seppur.2011.09.013-   Thomas, R. M., Keitz, B. K., Champagne, T. M., & Grubbs, R. H.    (2011). Highly selective ruthenium metathesis catalysts for    ethenolysis. Journal of the American Chemical Society, 133(19),    7490-6. doi:10.1021/ja200246e-   U.S. Pat. No. 6,861,551.pdf. (n.d.).-   U.S. Pat. No. 7,943,560 Cyclopropane.pdf. (n.d.).-   Wille, J. J., & Kydonieus, A. (2003). Palmitoleic acid isomer    (C16:1delta6) in human skin sebum is effective against gram-positive    bacteria. Skin Pharmacology and Applied Skin Physiology, 16(3),    176-187. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12677098-   Yang, B., & Kallio, H. P. (2001). Fatty acid composition of lipids    in sea buckthorn (Hippophae rhamnoides L.) berries of different    origins. Journal of agricultural and food chemistry, 49(4), 1939-47.    Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11308350-   Zabeti, M., Wan Daud, W. M. A., & Aroua, M. K. (2009). Activity of    solid catalysts for biodiesel production: A review. Fuel Processing    Technology, 90(6), 770-777. Elsevier B. V.    doi:10.1016/j.fuproc.2009.03.010

1-20. (canceled)
 21. A method of producing α-olefins, comprising:producing esters from a composition comprising at least 50 mass % ofpalmitoleic acid and oleic acid; and reacting at least a portion ofesters in a metathesis reaction with ethene to produce a reactionmixture comprising 1-octene (C8H16), 1-decene (C10H20), andethyl-9-decenoate (C12H22O2).
 22. The method of claim 21, wherein thecomposition comprises about equal parts palmitoleic acid and oleic acid.23. The method of claim 21, wherein the composition comprises a greaterportion of palmitoleic acid than oleic acid.
 24. The method of claim 21,wherein the composition comprises a greater portion of oleic acid thanpalmitoleic acid.
 25. The method of claim 21, wherein the metathesisreaction comprises a catalytic system selected from the group consistingof: WC16/Me4Sn; Heterogeneous Re2O7/Al2O3; HeterogeneousRe2O7/SiO2.Al2O3/SnBu4; W(O-2,6-C6H3X2)2C14 (X═Cl, Ph) precatalystpromoted with Me4Sn; B2O3.Re2O7/Al2O3.SiO2/SnBu4; WC16 and WOC14, asprimary catalysts and SnMe4, PbMe4, Cp2TiMe2, and Cp2ZrMe2, ascocatalysts; Ruthenium based catalyst; Grubb's catalyst firstgeneration; Grubbs catalyst second generation; and Hoveyda-Grubbscatalyst.
 26. The method of claim 21, wherein the palmitoleic acid andoleic acid are extracted from algae.
 27. The method of claim 21, furthercomprising reacting at least a portion of this reaction mixture (or aderivative thereof) in a condensation reaction.
 28. The method of claim27 wherein the condensation reaction is a Ti-Claisen condensation with acatalysis system selected from the group consisting of: TiCl₄—Bu₃N,Pentafluorophenylammonium Triflate, and MgBr₂.OEt₂ in DIPEA.
 28. Themethod of claim 27 wherein the condensation reaction produces acondensation product comprising a beta-ketoester, and further comprisingconducting a metathesis reaction of the condensation product to produceethene and a macrocyclic compound.
 29. The method of claim 28 whereinthe ethene produced is recycled to the step of reacting the esters ofpalmitoleic acid and oleic acid in a metathesis reaction with ethene.30. The method of claim 28 wherein the macrocyclic compound is2-ethoxycarbonyl-9-cycloheptadecenone.
 31. The method of claim 21,wherein the yield of ethyl 9-decenoate is in the range of 35 to 60%.